Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Anatomy and Cell Biology

Supervisor

Dr. Whitehead, Shawn N.

2nd Supervisor

Dr. Walton, Paul

Co-Supervisor

Abstract

Disruption of the blood-brain barrier (BBB) contributes to cerebral small vessel disease (cSVD) by facilitating plasma protein extravasation, including fibrinogen. Fibrinogen activates microglia into a pro-inflammatory state via CD11b/CD18 signaling. However, the effects of prolonged fibrinogen exposure on microglial function remain unclear. This study is the first to develop an in vitro model for cSVD by culturing BV-2 microglia for 7 days to investigate the impact of prolonged fibrinogen exposure, simulating conditions of chronic BBB disruption. The results demonstrated that repeated fibrinogen exposure induced sustained inflammation, oxidative stress, and a senescence-like phenotype in BV-2. Interestingly, prolonged in vitro culture alone resulted in dysfunction characterized by impaired mitochondrial function and senescence markers. This suggests that extended culture conditions can mimic aging-like effects on microglia. These findings highlight the dual impact of fibrinogen exposure and prolonged culture duration on microglial function, providing new insights for future studies on microglial dysfunction in cSVD.

Summary for Lay Audience

The blood-brain barrier (BBB) is a protective barrier in the brain that helps keep harmful substances out. When this barrier breaks down, as seen in conditions like hypertension, diabetes, smoking, aging, and under the umbrella term cerebral small vessel disease (cSVD), blood proteins like fibrinogen can leak into the brain. As a result, a key brain cell responsible for maintaining balance and health, called microglia, becomes active. Microglia are crucial cells in the brain that help protect it from damage. Previous studies have shown that fibrinogen can activate microglia, leading them to create an inflammatory environment in the brain. This response is initially helpful in managing the stress caused by external factors, like fibrinogen. However, prolonged activation of microglia can become problematic. Continuous microglia activation by various factors exacerbates inflammation in the brain, which can cause irreversible damage to other brain cells, such as neurons, that are essential for brain function and cognition. It remains unclear whether ongoing exposure of microglia to fibrinogen can turn microglia into a threat to the brain. This study aims to answer this question by designing an experiment to simulate this condition outside of the brain, addressing this knowledge gap. Given the rising prevalence of conditions that increase fibrinogen levels in the brain (such as diabetes, etc.), this study could provide valuable insights for future therapeutic approaches.

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Available for download on Friday, February 06, 2026

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